Key Points:
- CTX310 is a first-in-class in vivo CRISPR-Cas9 therapy designed to permanently disrupt hepatic ANGPTL3, a gene that regulates lipid metabolism.
- In the Phase 1 CRISP-ANGPTL3 trial, a single infusion of CTX310 safely reduced ANGPTL3 levels by up to 80%, LDL-C by 49%, and triglycerides by 55% at 60 days.
- No dose-limiting toxicities or serious treatment-related adverse events were observed across escalating doses up to 0.8 mg/kg.
Despite decades of lipid-lowering therapies, adherence and lifelong treatment remain major barriers in managing atherosclerotic cardiovascular disease. A therapy capable of permanently lowering LDL cholesterol and triglycerides after a single dose could transform preventive cardiology.
At the 2025 American Heart Association Scientific Sessions, Dr. Steven E. Nissen presented the Phase 1 CRISP-ANGPTL3 trial, simultaneously published in The New England Journal of Medicine. The study evaluated CTX310, a lipid nanoparticle–delivered CRISPR-Cas9 system developed by CRISPR Therapeutics, which edits the ANGPTL3 gene directly in hepatocytes to permanently disable its function.
CRISP-ANGPTL3 (ACTRN12623000809639) was a multicenter, open-label, ascending-dose Phase 1 trial conducted across Australia, New Zealand, and the UK. Fifteen adults (ages 31–68) with uncontrolled hypercholesterolemia, mixed dyslipidemia, or severe hypertriglyceridemia, despite maximally tolerated lipid-lowering therapy, received a single IV dose of CTX310 at one of five escalating levels: 0.1, 0.3, 0.6, 0.7, or 0.8 mg/kg of estimated lean body weight. All participants were maintained on stable background lipid-lowering therapy throughout follow-up. The primary endpoint was adverse events, including dose-limiting toxic effects, and secondary endpoints included percent changes from baseline in ANGPTL3, LDL-C, triglycerides, and apolipoprotein B over 60–90 days.
CTX310 was well tolerated at all dose levels. No dose-limiting toxicities occurred. Mild, transient infusion reactions (20%) and short-lived aminotransferase elevations (7%) resolved without sequelae. One death occurred 179 days after the lowest dose. At higher doses, results were striking as ANGPTL3 levels were lowered by 73–80%, LDL cholesterol by 48.9%, triglycerides by 55.2%, whereas apolipoprotein B levels were reduced by 33.4%.
For patients with familial hypercholesterolemia, severe hypertriglyceridemia, or refractory mixed dyslipidemia, CTX310 could represent a paradigm shift: a one-time genetic intervention instead of lifelong pharmacotherapy. If validated in larger phase 2–3 trials, this strategy could usher in a new era of gene-editing–based cardiovascular prevention.
The authors conclude that “a single infusion of CTX310 produced lipid reductions comparable to potent chronic therapies, with the potential for long-term benefit”. These findings establish the first human proof-of-concept for in vivo CRISPR-Cas9 gene editing of a cardiovascular/metabolic target. Importantly, investigators stressed the need for long-term surveillance for up to 15 years which will allow for the monitoring of durability and safety, including risks of off-target edits or delayed toxicity.